Confusion persists over pathogenesis of spondylolysis. To confirm pathogenicity of the previously identified causative mutation of spondylolysis and investigate the genetic etiology, we generate a new mouse line harboring D673V mutation in the Slc26a2 gene. D673V mutation induces delayed endochondral ossification characterized by transiently reduced chondrocyte proliferation in mice at the early postnatal stage. Adult D673V homozygotes exhibit dysplastic isthmus and reduced bone volume of the dorsal vertebra resembling the detached vertebral bony structure when spondylolysis occurs, including the postzygopophysis, vertebral arch, and spinous process, which causes biomechanical alterations around the isthmic region of L4-5 vertebrae indicated by finite element analysis. Consistently, partial ablation of Slc26a2 in vertebral skeletal cells using Col1a1-Cre; Slc26a2 fl/fl mouse line recapitulates a similar but worsened vertebral phenotype featured by lamellar isthmus. In addition, when reaching late adulthood, D673V homozygotes develop an evident bone-loss phenotype and show impaired osteogenesis. These findings support a multifactorial etiology, involving congenitally predisposed isthmic conditions, altered biomechanics, and age-dependent bone loss, which leads to SLC26A2-related spondylolysis.
Keywords: SLC26A2; bone loss; isthmic defect; spondylolysis; vertebral development.
© 2019 Federation of American Societies for Experimental Biology.